Although effective antiretroviral therapy prevents AIDS and other complications, it does not completely restore health. The excess morbidity that occurs during treatment is due to several factors, including direct drug- toxicity, persistent viral replication/production and high levels of HIV-associated inflammation. Hence, strategies aimed at achieving complete viral eradication may be needed in order to fully restore health among HIV infected individuals. One of the major barriers to pursuing studies of eradication is the lack of a complete understanding regarding the interaction between disease stage, inflammation and viral persistence. Also, no assay of viral persistence amendable to larger clinical studies has been developed and validated. It is the central premise of this application that heightened inflammation during long-term therapy is both a cause and consequence of viral persistence, and that strategies aimed at eradicating HIV will require focused efforts aimed at reducing this inflammation. It is also a major premise of this application that a well validated, high throughput assay that can either directly or indirectly measure the size of the latent reservoir will be needed before any clinical trials can be performed. To address these objectives we propose an intensive investigation of HIV viral reservoirs and inflammation in a well characterized cohort of HIV infected patients. Sixty patients who received therapy during acute, early and late infection will be included, as the host/virus dynamics likely differ in these three patient populations. In Aim 1 we will measure quantify proviral HIV DNA, ultrasensitive plasma HIV RNA, cell-based RNA, and episomal DNA during five years of effective antiretroviral therapy. In Aim 2 we will measure the HIV associated host responses over five years. For each aim, the primary outcome measure will be the level of replication competent HIV in blood and gut mucosa at or after year five of therapy. Finally, in Aim 3 we will determine the distribution of HIV in various T cell subsets, and define the relationship between inflammation and HIV distribution. Several novel hypotheses will be addressed in each aim. Knowledge gained regarding the natural history of treated HIV infection will provide valuable information for the design and implementation of large scale eradication studies. Knowledge gained from this study may also resolve many of the uncertainties regarding the role of chronic inflammation in driving viral persistence, and hence could lead to the development of novel interventions. PUBLIC HEALTH RELEVANCE: Although effective antiretroviral therapy prevents AIDS and other complications, it does not completely restore health. The excess morbidity that occurs during treatment is due to several factors, including direct drug- toxicity, persistent viral replication/production and high levels of HIV-associated inflammation. We will define which of the many ways to measure viral persistence predicts the degree of replication competent virus (in blood and mucosa tissues), and determine how HIV is distributed among T cell subsets, as well as the effect that disease stage and inflammation has on this distribution. Our work may also provide important insights in the role of chronic inflammation in driving viral persistence, and hence may lead to the development of novel interventions.